Amyl nitrite inhalant composition



United States Patent 6 3,106,511 AMYL NITRETE INHALANT CGMPGSITIQN HarryA. 'Cuttler, Gien Cove, and Herman E. Jass, Hartsdaie, Nfifl, assignorsto Revlon, Inc, New York, N311, a corporation of Deiaware No Drawing.Filed Dec. 14, 1961, Ser. No. 159,462

9 Claims. (Q1. 167-54) This invention relates to medicament compositionscontaining amyl nitrite, and to their preparation and use. Inparticular, this invention relates to self-propelling medicamentcompositions containing amyl nitrite and adaptable to dispersion inaerosol form, and to their preparation and use.

The use of amyl nitrite as a vasodilator in the treatment of anginapectoris is well known in the art. Treatment using this drug is commonlyby inhalation, and the drug is usually marketed in sealed breakableampoules or pearls. When chest pain occurs, a patient employing the drugbreaks the ampoule wrapped in a handkerchief and inhales the fumes ofthe drug.

This method of treatment suffers from a number of disadvantages. First,it is almost imposible properly to dose a patient with the drug by thistechnique, since the amount of drug inhaled will vary greatly with themanner of inhalation, such as the depth of breathing and the distance atwhich the source of the drug is held from the nose and mouth. Also, toinsure that an adequate dosage of the drug is delivered to the patient,the ampoules must containwastefully large amounts of the drug, usually200300 mg., which amount far exceeds the required dose. Further, thedrug has a characteristic and offensive odor which may make its use inpublic inconvenient and embarrassing. Also, the inconvenience ofpackaging, merchandising, and carrying breakable ampoules isselfevident. Further, amyl nitrite vapors are inflammable, andinhalation of the vapors involves some risk.

However, the most important impediments to the medicinal use of amylnitrite are its characteristic unpleasant taste and odor, which commonlycause nausea, vomiting, and headaches in many patients who ingest thedrug. These side effects of the drug have heretofore hindered its use,even though the problems of inconvenient administration ofthe drug canbe overcome by dispensing it in aerosol form, for example.

According to the present invention, it has been discovered that thedisagreeable'taste and odor of amyl nitrite can be eilectively masked toreduce or eliminate the disagreeable side eflects often caused by thedrug.

Although the masking agent may be combined with amyl nitrite foradministration by conventional inhalation or other means, the greatestsignificance of the discovery is that it makes possible the practicaladministration of amyl nitrite by aerosol inhalation.

The masking agent of the invention is a critical combination ofperforming and flavoring agents. In particular, the disagreeable tasteand odor of amyl nitrite are effectively masked with ionones. Manyionone isomers, including the alpha, beta-, gamma-, and deltaetc.isomers, are known to the art and can be employed either alone or inmixtures containing two or more components in all proportions.Similarly, the isomeric methyl and allyl ionones can be employed, eitheralone, in admixture in all proportions with one another, or in admixturein all proportions with any and all of the unsubstituted ionone isomers.

These ionones have been used in the prior art in perfumery, and, incombination with sweetening agents, in small amounts as flavoring agentsin hard candies, cough syrups and other artificially flavored materials.The ionones, undiluted, have a bitter and disagreeable taste,

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however, and because of this property the prior art has not heretoforeemployed them in the relatively large amounts in which they are used inthe present invention, where they are not combined with sweeteners.

In the masking agent of the invention, these ionone materials arecritically employed in combination with the so-called Cl4, C16, and Cl8aldehydes, also known in the perfuming art. As known in the art, thesevarious aldehydes are compounds, not necessarily aldehydes, which havecommon characteristic properties useful in flavoring and perfuming. TheCl4 or peach aldehydes, for example, include gamma-undecalactone,delta-undecalactone, gamma-decalactone, and alpha-substituted gammabutyrolactones in which the substituents may be aliphatic, such asallyl, propyl, heptyl, and octyl, or aromatic, such as phenyl, benzyl,and citronellyl. Those skilled in the art recognize that these Cl4 materials may contain more or fewer than 14 carbon atoms.

' Similarly, the C16 or strawberry aldehydes include materials such asethyl-phenyl-glycidate and ethyl-methylphenl-glycidate.

The C18 or coconut aldehydes include octalactone,

.gamma-nonyllactone, gamma-substituted gamma-butyrolactones such asgammacaprylolactone, gamma-n-amyl butyrolactone, and8-methyl-l,4-octanolide.

These perfuming agents, together with other optional perfuming agents ofa wide variety, are critically combined with a flavoring agent aidingthe masking of the taste and odor of amyl nitrite and additionallymasking the often disagreeable taste of the perfuming agents principallyemployed to mask the drug. As flavoring agents, agents from theso-called mint series are critically present, but can be used incombination with numerous other flavoring agents, preferably those fromthe so-called spice series, but also including fruit flavors, aniseflavors (lic 'orice, anethol, etc), root extracts, and/or Wintergreen,

critically contains between about 7.5 and about 22.5 percent by weight,based on the total masking agent composition, preferably about 10-20percent by weight, of ionone and/or methyl ionone and/or allyl iononeisorners. These materials are critically combined with between about 0.5and about 2.5 percent by weight, preferably about 1 to about 2 percentby weight, of the socalled Cl4 to (3-18 aldehydes, alone or incombination. The composition also critically contains between about 45and about 70 percent by weight of a flavoring agent from the mintseries, preferably about 50 to percent by weight of such a flavoringagent. In addition, other perfumi-ng agents, well known to those skilledin the art, may be present in amounts of up to 8 percent by weight,suitably from about 6 to about 8 percent by weight, or 6.5 to 7.5percent by weight of the composition. Also, other flavoring agents wellknown to those skilled in the art may be present in amounts of up to 30percent by weight, suitably from 10 to 30 percent by weight, or 12 to 25percent by weight of the composition. 1

Many flavoring agents in the so-called =rnint series are known to theflavoring chemist. This series includes spearmint oil, USP, peppermintoil, USP, terpeneless peppermint, terpeneless spearrnint, menthol,synthetic menthols, and others.

As additional flavoring agents may be mentioned substances in the so-called spice series suchas cassia, USP, clove bud oil, USP, eugenol,nutmeg oil, cinnamic aldehyde, methyl cinnamic aldehyde, as well asother flavoring agents such as vanillin, ethyl vanillin, heliotropin,methyl salicylate, sweet birch oil, and various esters of aromaticalcohols *and/ or acids such as methyl'anthranilate, or other esters ofanthranilic, benzoic, salicylic, and

cinnamic acids, or benzyl, and cinnarnyl alcohols, and the like.Additional flavoring agents may be found in the fruit flavors, such asorange, lemon, lime, the anise flavors, the root extracts, Wintergreen,and others.

As additional perfuming agents useful in the compositions of theinvention may be mentioned materials such as iso-eugenol, benzylacetate, linalool, geranyl acetate, rose oil, and the like.

The above listing of perfuming and flavoring agents, including materialsin the mint series, spice series, and others, is not intended to beexhaustive. Numerous other flavoring and perfuming agents are known tothose skilled in the art and are comprised within the scope of thepresent invention. Specific reference is made to Synthetic FoodAdju-ncts, by Morris B. Jacobs, D. Van Nest-rand, New York (1947), andPerfume and Flavor Materials of Natural Origin, by Steflan Arctander,published by the author, Elizabeth, New Jersey (1960), where numerousmaterials known to the art and suitable for use in the invention arediscussed.

To prepare a masked amyl nitrite composition, the pre-cornpoundedmasking agent, prepared by thorough mixing of the flavoring andperfuming ingredients, is suitably combined with amyl nitrite in amountsof from about 0.5 to about 4 percent by Weight of amyl nitrite,preferably in amounts of from 1 to 3 percent by weight of amyl nitrite.The final composition, with an aerosol propellant, suitably contains aminimum of about 0.1 perent by weight of masking agent.

In preparing an aerosol composition, the masking agent and amyl nitriteare dissolved in a non-toxic volatile liquefied propellant. Suitablenon-toxic volatile propellants are known in the art, and are discussedin Patent 2,868,691 for example. These materials are generallyfluorinated or fluorochlorinated lower saturated aliphatic hydrocarbons,suitably halogenated alka-nes containing one to four carbon atoms,preferably one or two carbon atoms, and at least one fluorine atom. Ingeneral, any of the materials disclosed in the earlier mentioned patentcan be employed according to the present invention, includingpropellants such as dichlorodifluoromethane (Freon 12),dichlorotetrafluoroethane (Freon 114), trichloromonofluoromethane (Freon11), and octafluorocyclobutane (Freon C-3l8). These propellants, orsuitable mixtures thereof, will produce a propellant vapor pressurebetween about 25 and about 60 pounds per square inch at roomtemperatures (20-25 C.). Suitable mixtures of the propellants can beemployed to give a preferred vapor pressure between about 35 and about40 pounds per square inch at these temperatures. The best propellantcompositions contain about 60 percent by weight of Freon 12, blendedwith Freon 114. However, this mixture or other specific mixtures are notcritical to the invention and any non-toxic liquid volatile propellant,such as those earlier described herein, may be employed.

The products of the invention are conveniently used in aerosolcontainers having a metered valve which dispenses a controlled quantityof the self-propelling aerosol composition as a single dose. Thesecontainers are well known in the art, and may be made of any material,such as glass, plastic, or metal, adequate to contain the pressuresgenerated by the volatile propellant materials therein. Conventionally,these metered containers have an internal well of predetermined volumewhich is filled with the self-propelling composition. On activation ofthe aerosol valve, only this predetermined volume of self-propellingcomposition is dispersed as an aerosol, and the internal well isrefilled.

When used in such a metered valve container, the relative proportion ofamyl nitrite (and masking agent) to volatile propellant may vary withthe dose of pure amyl nitrite to be dispensed and the size of themetered dose delivered by the valve. Dosage rates of pure amyl nitritewill vary between about 1 milligram and about 25 milligrams, generallybetween about 5-10 milligrams, and the quantity of propellant combinedtherewith will be chosen to deliver this amount of pure amyl nitrite onactivation of a metered valve of chosen size. For example, in meteredaerosol dispensers having a so-called 50 milligram valve, that is, avalve which will dispense 50 milligrams of a liquid of unit density eachtime it is activated, amyl nitrite is usually combined with a propellantin amounts of between about 5 and about 20 percent, suitably about 10percent by weight, based on the total composition. In such a combinationcontaining 10 percent by weight of amyl nitrite, about 0.5 to 0.4percent by weight of masking agent, usually between about 0.1 and 0.3percent by weight, is present, the balance being the volatile propellantmixture.

A better understanding of the invention and of its many advantages willbe had by referring to the following specific examples, given by way ofillustration.

Example The following masking agents were prepared by mixing theenumerated ingredients in the amounts indicated.

Parts by weight A. Ionones: 11-13 methyl ionone 2000 B. Mint flavors:

Spearmint oil, USP 2000 Peppermint oil, USP 5000 Menthol 2000 C.C-14--C-18 aldehydes: C-14 aldehyde 150 D. Other flavoring agents:

Cassia, USP 1000 -Eugeno1 500 Vanillin 500 Heliotropin 500 Methylanthranilate E. Other perfuming agents:

Benzyl acetate 500 Rose oil 500 A. Ionones:

a-flionone 1000 11-13 methyl ionone 1500 B. C-l4-C18 aldehydes:

C-l4 aldehyde 100 C-l8 aldehyde 50 C. Mint flavors:

Spearmint oil, USP 3000 Peppermint oil, USP 2000 Terpeneless Spearmint1000 Menthol 3000 D. Other flavoring agents:

Cassia, USP 500 Clovebud oil, USP 500 Nutmeg oil 500 Vanillin 200 Ethylvanillin 200 Heliotropin 400 E. Other perfuming agents:

Benzyl acetate 400 Lin-alool 100 Geranyl acetate 100 Rose oil 400 A.Ionones:

a-fi ionone 600 a-fi methyl ionone 1500 B. C14- Cl8 aldehydes: C-l4aldehyde C. Mint flavors:

Peppermint oil, USP 3000 Terpeneless peppermint 1000 Menthol 2000 D.Other flavoring agents:

Cassia, USP 500 Cinnamic aldehyde 300 Vanillin 500 Heliotropin 400Methyl salicylate 500 Sweet birch oil 100 Methyl anthranilate 50 E.Other perfurning agents:

Benzyl acetate 400 Rose oil 400 These masking agents were used tocompound aerosol compositions with amyl nitrite as follows.

Ingredients: Parts by weight Masking agent 0.25 Amyl nitrite 9.75 Freon12 54 Freon 114 36 Ingredients: Parts by weight Masking agent 0.30 Amylnitrite 14.70 Freon 12 60 Freon 114 15 Freon 11 Ingredients: Parts byWeight Masking agent 0.20 Amyl nitrite 6.80 Freon 12 53 Freon 114 30Freon C-318 10 Although specific embodiments have been shown anddescribed, it is to be understood that they are illustrative, and arenot to be construed as limiting on the scope and spirit of theinvention.

What is claimed is:

1. A composition suitable for inhalation therapy consisting of amylnitrite and a masking agent comprising a blend of (A) a member selectedfrom the group consisting of ionone, methyl ionone, and allyl iononeisomers, (B) a perfuming agent selected from the group consisting of theC-14, C-l6, and C18 aldehydes, and (C) a flavoring agent of the mintseries.

2. A composition as in claim 1 wherein said masking agent is present inan amount of at least 0.5 percent by weight of amyl nitrite.

3. A composition as in claim 1 in a non-toxic liquefied propellant.

4. A composition as in claim 1 wherein additional flavoring andperfuming agents are present. 1

5. A composition as in claim 4 wherein said propellan comprises 60percent by Weight of dichlorodifiuoromethane, the balance beingdichlorotetrafluoroethane.

6. In a composition adaptable to use in inhalation therapy in aerosolform and comprising amyl nitrite in a non-toxic liquefied propellant, amasking agent combined in said composition and consisting essentially ofa blend of:

(A) between about 7.5 and 22.5 percent by weight of a member selectedfrom the group consisting of ionone, methyl ionone, and allyl iononeisomers;

(B) between about 0.5 percent to about 2.5 percent by weight of aperfuming agent selected from the group consisting of the C-14, C-16,and C-18 aldehydes;

(C) between about 45 percent and about 75 percent of a flavoring agentof the mint series;

(D) up to about 8 percent by weight of other optional perfuming agents;and

(E) up to about percent by Weight of other optional flavoring agents,all percentages being based on the weight of the blend.

7. A composition as in claim 6 wherein said masking agent is present inan amount of at least 0.5 percent I by weight of amyl nitrite.

8. The method of masking the disagreeable taste and odor of amyl nitritewhich comprises combining therewith from about 0.5 to about 4 percent,by weight of amyl nitrite, of a masking agent comprising a blend of (A)a member selected from the group consisting of ionone, methyl ionone,and allyl ionone isomers, (B) a perfuming agent selected from the groupconsisting of the C-14, C-16, and C-18 aldehydes, and C a flavoringagent of the mint series.

9. The method as in claim 8 wherein said amyl nitrite and masking agentare dispersed in a non-toxic liquefied propellant.

References Cited in the file of this patent FOREIGN PATENTS 461,813Canada Dec. 20, 1949 OTHER REFERENCES U.S. Dispensatory, 25th edition,1955, pages 89 and 90 Lippincott Co., Phila., Pa.

Pharmaceutical Formulas, vol. 1, 12th edition, 1953, The Chemist andDruggist, London, England, pages 648- 650.

Shepherd: Aerosols: Science and Technology, 1961, IntersciencePublishers, Inc., N.Y., N.Y., pages 293, 294, 298, and 311.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N00 3106,511 October 8 1963 Harry A. Cutt ler et a1.

he above numbered pat- It is hereby certified that error appears in 1:

Patent should read as ent requiring correction and that the said Letterscorrected below.

Column 6, line 3. for the claim reference numeral "4" read 6 same column'6, lines 35 and 36 ing agent read (C) e filBVOIiflQ agent Signed andsealed this IZth day of May 1964;

(SEAL) Attest:

ERNEST Wo SWIDER EDWARD J BRENNER Attesting Officer Commissioner ofPatents for "C a flavor"-

1. A COMPOSITION SUITABLE FOR INHALATION THERAPY CONSISTING OF AMYLNITRITE AND A MASKING AGENT COMPRISING A BLEND OF (A) A MEMBER SELECTEDFROM THE GROUP CONSISTING OF IONONE, METHYL IONONE, AND ALLYL IONONEISOMERS, (B) A PERFUMING AGENT SELECTED FROM THE GROP CONSISTING OF THEC-14, C-16, AND C-18 ALDEHYDES, AND (C) A FLAVORING AGENT OF THE MINTSERIES.